Lysosome-targeting chimeras (LYTACs) have emerged as a revolutionary targeted protein degradation (TPD) technology in modulating the levels of extracellular and membrane proteins. However, lack of lysosome-trafficking receptors (LTRs) limits the development of LYTACs. Here, we firstly confirm that folate receptor α (FRα) is a new generation of lysosome-targeting receptor (LTR) of LYTAC, facilitating the transport of membrane proteins to lysosomes to realize degradation. Moreover, novel FRTACs are constructed by a new “polyvalent crosslinking strategy”, instead of the traditional “one folate conjugating one drug strategy”. Polyvalency creates avidity, allowing FRTACs crosslinking FRα to dramatically improve the degradation efficiency. As a result, the optimized FRTACs, including EGFR-targeting FR-Ctx, PD-L1-targeting FR-Atz, TROP2-targeting FR-Stz, and HER2-targeting FR-Ttz, successfully eliminate cell surface targets with a subnanomole activity. Mechanism investigation reveals that FRTACs trigger targets degradation in a FRα- and lysosomal-dependent manner. Besides, FR-Ctx reduces cancer cell proliferation, and FR-Atz increases the cytotoxicity of T cells toward tumor cells. Furthermore, FR-Atz exhibits potent degradation efficiency of PD-L1 in vivo and elicits tumor-specific immune responses by switching the tumor immune microenvironment from a suppressed state to an activated state in both RM-1 mice model and humanized PD-1/PD-L1 B16F10 mice model. To our knowledge, FRTACs are the most potent protein degrader ever reported. The novel FRTACs will expand the application of FRα and provide a new platform for designing tumor-targeting LYTACs.